| In this study I examined the role of IRF-4, an immune system specific transcription factor, in two important aspects of B cell biology: B cell receptor (BCR) editing and B cell tumorigenesis.;Receptor editing is the primary means through which B cells revise antigen receptors and maintain tolerance against self-antigens. Previous studies have demonstrated that IRF-4 promotes immunoglobulin light chain rearrangement and transcription at the pre-B cell stage. Here, the role of IRF-4 in receptor editing was analyzed. Using BCR transgenic mice, I showed that secondary rearrangement triggered by membrane bound antigen is defective in IRF-4 deficient mice. The defect in secondary rearrangement is more severe at the immunoglobulin lambda locus than at the kappa locus, indicating that IRF-4 is more critical for lambda rearrangement. Furthermore, the expression of IRF-4 is rapidly induced in immature B cells by self antigen, and reconstitution of IRF-4 expression in IRF-4 mutant immature B cells promotes secondary rearrangement. Thus, my studies identify IRF-4 as a nuclear effector of a BCR signaling pathway that promotes secondary rearrangement at the immature B cell stage.;Previous studies have shown that IRF-4 acts as a negative regulator of early B cell proliferation. However, neither IRF-4+/- nor IRF-4-/- mice exhibit B cell transformation. Here, I studied whether absence of IRF-4 in synergy with other genetic defect could lead to B cell transformation. Using c-Myc overexpressing mice I showed that heterozygous loss of IRF-4 is enough to exacerbate c-Myc-induced tumorigenesis, leading to aggressive leukemia of large, cycling pre-B cell origin and accelerated mortality. These leukemic cells exhibited a reduced level of apoptosis through hyperactivation of the canonical Wnt signaling pathway, which may be responsible for their rapid transformation. Therefore, this study demonstrated that IRF-4 takes part in an important anti-tumor mechanism to protect against early B cell transformation. |
